bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒01‒01
38 papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. Genomics and phenomics of body mass index reveals a complex disease network.
  2. Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.
  3. Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
  4. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis.
  5. Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19.
  6. The lipid transporter ORP2 regulates synaptic neurotransmitter release via two distinct mechanisms.
  7. UCP2-dependent redox sensing in POMC neurons regulates feeding.
  8. The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival.
  9. Molecular and spatial signatures of mouse brain aging at single-cell resolution.
  10. Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing.
  11. Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.
  12. Three-dimensional wide-field fluorescence microscopy for transcranial mapping of cortical microcirculation.
  13. TRPM7 kinase is required for insulin production and compensatory islet responses during obesity.
  14. A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation.
  15. Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue.
  16. Genetic dissection of intercellular interactions in vivo by membrane-permeable protein.
  17. Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats.
  18. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.
  19. SREBP signaling is essential for effective B cell responses.
  20. Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis.
  21. Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.
  22. ADAM10- and γ-secretase-dependent cleavage of the transmembrane protein PTPRT attenuates neurodegeneration in the mouse model of Alzheimer's disease.
  23. Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
  24. Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch.
  25. Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling.
  26. Piezo mechanosensory channels regulate centrosome integrity and mitotic entry.
  27. Clonal replacement sustains long-lived germinal centers primed by respiratory viruses.
  28. MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome.
  29. P2Y6 receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging.
  30. An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia.
  31. SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.
  32. Bone marrow-derived IGF-1 orchestrates maintenance and regeneration of the adult skeleton.
  33. The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer.
  34. Deconstructing body axis morphogenesis in zebrafish embryos using robot-assisted tissue micromanipulation.
  35. Molecular mechanism of substrate recognition by folate transporter SLC19A1.
  36. SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression.
  37. Elevated Adipocyte Membrane Phospholipid Saturation Does not Compromise Insulin Signaling.
  38. SPOP loss of function protects against tauopathy.
  1. Nat Commun. 2022 Dec 29. 13(1): 7973
    Genomics and phenomics of body mass index reveals a complex disease network.
    VA Million Veteran Program
      Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.
    DOI:  https://doi.org/10.1038/s41467-022-35553-2
  2. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2209062120
    Atf7ip and Setdb1 interaction orchestrates the hematopoietic stem and progenitor cell state with diverse lineage differentiation.
    Jiaxin Wu, Juan Li, Kang Chen, Guolong Liu, Yating Zhou, Wenqi Chen, Xiangzhan Zhu, Terri T Ni, Bianhong Zhang, Daqing Jin, Dali Li, Lan Kang, Yuxuan Wu, Ping Zhu, Peng Xie, Tao P Zhong.
      Hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous group of cells with expansion, differentiation, and repopulation capacities. How HSPCs orchestrate the stemness state with diverse lineage differentiation at steady condition or acute stress remains largely unknown. Here, we show that zebrafish mutants that are deficient in an epigenetic regulator Atf7ip or Setdb1 methyltransferase undergo excessive myeloid differentiation with impaired HSPC expansion, manifesting a decline in T cells and erythroid lineage. We find that Atf7ip regulates hematopoiesis through Setdb1-mediated H3K9me3 modification and chromatin remodeling. During hematopoiesis, the interaction of Atf7ip and Setdb1 triggers H3K9me3 depositions in hematopoietic regulatory genes including cebpβ and cdkn1a, preventing HSPCs from loss of expansion and premature differentiation into myeloid lineage. Concomitantly, loss of Atf7ip or Setdb1 derepresses retrotransposons that instigate the viral sensor Mda5/Rig-I like receptor (RLR) signaling, leading to stress-driven myelopoiesis and inflammation. We find that ATF7IP or SETDB1 depletion represses human leukemic cell growth and induces myeloid differentiation with retrotransposon-triggered inflammation. These findings establish that Atf7ip/Setdb1-mediated H3K9me3 deposition constitutes a genome-wide checkpoint that impedes the myeloid potential and maintains HSPC stemness for diverse blood cell production, providing unique insights into potential intervention in hematological malignancy.
    Keywords:  HSPC; epigenetics; leukemia; myeloid differentiation; retrotransposon
    DOI:  https://doi.org/10.1073/pnas.2209062120
  3. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01771-5. [Epub ahead of print]41(13): 111875
    Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
    Nandhitha Uma Naresh, Sookyung Kim, Tomer Shpilka, Qiyuan Yang, Yunguang Du, Cole M Haynes.
      Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPRmt), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPRmt in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.
    Keywords:  ATFS-1; C. elegans; CP: Metabolism; CP: Molecular biology; DAF-2; UPR; UPRmt; insulin receptor; mitochondria; mtDNA; starvation; stress response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111875
  4. Nat Commun. 2022 Dec 27. 13(1): 7965
    The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis.
    Zhi Lin, Jiao Liu, Fei Long, Rui Kang, Guido Kroemer, Daolin Tang, Minghua Yang.
      Ferroptosis is a type of regulated necrosis caused by unrestricted lipid peroxidation and subsequent plasma membrane rupture. However, the lipid remodeling mechanism that determines sensitivity to ferroptosis remains poorly understood. Here, we report a previously unrecognized role for the lipid flippase solute carrier family 47 member 1 (SLC47A1) as a regulator of lipid remodeling and survival during ferroptosis. Among 49 phospholipid scramblases, flippases, and floppases we analyzed, only SLC47A1 had mRNA that was selectively upregulated in multiple cancer cells exposed to ferroptotic inducers. Large-scale lipidomics and functional analyses revealed that the silencing of SLC47A1 increased RSL3- or erastin-induced ferroptosis by favoring ACSL4-SOAT1-mediated production of polyunsaturated fatty acid cholesterol esters. We identified peroxisome proliferator activated receptor alpha (PPARA) as a transcription factor that transactivates SLC47A1. The depletion of PPARA and SLC47A1 similarly sensitized cells to ferroptosis induction, whereas transfection-enforced re-expression of SLC47A1 restored resistance to ferroptosis in PPARA-deficient cells. Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway increased the anticancer activity of a ferroptosis inducer in mice. These findings establish a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance.
    DOI:  https://doi.org/10.1038/s41467-022-35707-2
  5. Nat Commun. 2022 Dec 26. 13(1): 7947
    Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19.
    Allison K Maher, Katie L Burnham, Emma M Jones, Michelle M H Tan, Rocel C Saputil, Laury Baillon, Claudia Selck, Nicolas Giang, Rafael Argüello, Clio Pillay, Emma Thorley, Charlotte-Eve Short, Rachael Quinlan, Wendy S Barclay, Nichola Cooper, Graham P Taylor, Emma E Davenport, Margarita Dominguez-Villar.
      Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.
    DOI:  https://doi.org/10.1038/s41467-022-35638-y
  6. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01778-8. [Epub ahead of print]41(13): 111882
    The lipid transporter ORP2 regulates synaptic neurotransmitter release via two distinct mechanisms.
    Marion Weber-Boyvat, Jana Kroll, Thorsten Trimbuch, Vesa M Olkkonen, Christian Rosenmund.
      Cholesterol is crucial for neuronal synaptic transmission, assisting in the molecular and structural organization of lipid rafts, ion channels, and exocytic proteins. Although cholesterol absence was shown to result in impaired neurotransmission, how cholesterol locally traffics and its route of action are still under debate. Here, we characterized the lipid transfer protein ORP2 in murine hippocampal neurons. We show that ORP2 preferentially localizes to the presynapse. Loss of ORP2 reduces presynaptic cholesterol levels by 50%, coinciding with a profoundly reduced release probability, enhanced facilitation, and impaired presynaptic calcium influx. In addition, ORP2 plays a cholesterol-transport-independent role in regulating vesicle priming and spontaneous release, likely by competing with Munc18-1 in syntaxin1A binding. To conclude, we identified a dual function of ORP2 as a physiological modulator of the synaptic cholesterol content and a regulator of neuronal exocytosis.
    Keywords:  CP: Neuroscience; ORP2; SNAP-25; SNARE; Stx1A; autapse; cholesterol; exocytosis; neurotransmitter release
    DOI:  https://doi.org/10.1016/j.celrep.2022.111882
  7. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01793-4. [Epub ahead of print]41(13): 111894
    UCP2-dependent redox sensing in POMC neurons regulates feeding.
    Nal Ae Yoon, Sungho Jin, Jung Dae Kim, Zhong Wu Liu, Qiushi Sun, Rebecca Cardone, Richard Kibbey, Sabrina Diano.
      Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.
    Keywords:  CP: Metabolism; CP: Neuroscience; NADH; UCP2; feeding behavior; glucose; hypothalamus; lactate; lipid utilization; mitochondria; pro-opiomelanocortin neurons; redox signaling
    DOI:  https://doi.org/10.1016/j.celrep.2022.111894
  8. Nat Immunol. 2022 Dec 29.
    The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival.
    Wen Lu, Ynes A Helou, Krishna Shrinivas, Jen Liou, Byron B Au-Yeung, Arthur Weiss.
      Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C-γ (PLCγ1) represents a critical step in T cell antigen receptor (TCR) signaling and subsequent thymocyte and T cell responses. PIP2 replenishment following its depletion in the plasma membrane (PM) is dependent on delivery of its precursor phosphatidylinositol (PI) from the endoplasmic reticulum (ER) to the PM. We show that a PI transfer protein (PITP), Nir3 (Pitpnm2), promotes PIP2 replenishment following TCR stimulation and is important for T cell development. In Nir3-/- T lineage cells, the PIP2 replenishment following TCR stimulation is slower. Nir3 deficiency attenuates calcium mobilization in double-positive (DP) thymocytes in response to weak TCR stimulation. This impaired TCR signaling leads to attenuated thymocyte development at TCRβ selection and positive selection as well as diminished mature T cell fitness in Nir3-/- mice. This study highlights the importance of PIP2 replenishment mediated by PITPs at ER-PM junctions during TCR signaling.
    DOI:  https://doi.org/10.1038/s41590-022-01372-2
  9. Cell. 2022 Dec 21. pii: S0092-8674(22)01523-9. [Epub ahead of print]
    Molecular and spatial signatures of mouse brain aging at single-cell resolution.
    William E Allen, Timothy R Blosser, Zuri A Sullivan, Catherine Dulac, Xiaowei Zhuang.
      The diversity and complex organization of cells in the brain have hindered systematic characterization of age-related changes in its cellular and molecular architecture, limiting our ability to understand the mechanisms underlying its functional decline during aging. Here, we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified changes in gene expression and spatial organization of major cell types in these regions over the mouse lifespan. We observed substantially more pronounced changes in cell state, gene expression, and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly enriched in the subcortical white matter, and identified both similarities and notable differences in cell-activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain.
    Keywords:  LPS; MERFISH; astrocyte; brain aging; inflammation; microglia; oligodendrocyte; single-cell RNA sequencing; single-cell transcriptomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2022.12.010
  10. Nat Commun. 2022 12 24. 13(1): 7939
    Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing.
    Xue Yue, Zhiyuan Xie, Moran Li, Kai Wang, Xiaojing Li, Xiaoqing Zhang, Jian Yan, Yimeng Yin.
      The interplay between histone modifications and DNA methylation drives the establishment and maintenance of the cellular epigenomic landscape, but it remains challenging to investigate the complex relationship between these epigenetic marks across the genome. Here we describe a nanopore-sequencing-based-method, nanoHiMe-seq, for interrogating the genome-wide localization of histone modifications and DNA methylation from single DNA molecules. nanoHiMe-seq leverages a nonspecific methyltransferase to exogenously label adenine bases proximal to antibody-targeted modified nucleosomes in situ. The labelled adenines and the endogenous methylated CpG sites are simultaneously detected on individual nanopore reads using a hidden Markov model, which is implemented in the nanoHiMe software package. We demonstrate the utility, robustness and sensitivity of nanoHiMe-seq by jointly profiling DNA methylation and histone modifications at low coverage depths, concurrently determining phased patterns of DNA methylation and histone modifications, and probing the intrinsic connectivity between these epigenetic marks across the genome.
    DOI:  https://doi.org/10.1038/s41467-022-35650-2
  11. Cell Metab. 2022 Dec 21. pii: S1550-4131(22)00542-3. [Epub ahead of print]
    Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.
    Ya-Ting Wang, Alissa J Trzeciak, Waleska Saitz Rojas, Pedro Saavedra, Yan-Ting Chen, Rachel Chirayil, Jon Iker Etchegaray, Christopher D Lucas, Daniel J Puleston, Kayvan R Keshari, Justin S A Perry.
      Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.
    Keywords:  apoptotic cell clearance; cellular adaptation; efferocytosis; homeostasis; metabolism; oxygen; pentose phosphate pathway; physiological hypoxia
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.005
  12. Nat Commun. 2022 Dec 28. 13(1): 7969
    Three-dimensional wide-field fluorescence microscopy for transcranial mapping of cortical microcirculation.
    Quanyu Zhou, Zhenyue Chen, Yu-Hang Liu, Mohamad El Amki, Chaim Glück, Jeanne Droux, Michael Reiss, Bruno Weber, Susanne Wegener, Daniel Razansky.
      Wide-field fluorescence imaging is an indispensable tool for studying large-scale biodynamics. Limited space-bandwidth product and strong light diffusion make conventional implementations incapable of high-resolution mapping of fluorescence biodistribution in three dimensions. We introduce a volumetric wide-field fluorescence microscopy based on optical astigmatism combined with fluorescence source localization, covering 5.6×5.6×0.6 mm3 imaging volume. Two alternative configurations are proposed exploiting multifocal illumination or sparse localization of point emitters, which are herein seamlessly integrated in one system. We demonstrate real-time volumetric mapping of the murine cortical microcirculation at capillary resolution without employing cranial windows, thus simultaneously delivering quantitative perfusion information across both brain hemispheres. Morphological and functional changes of cerebral vascular networks are further investigated after an acute ischemic stroke, enabling cortex-wide observation of concurrent collateral recruitment events occurring on a sub-second scale. The reported technique thus offers a wealth of unmatched possibilities for non- or minimally invasive imaging of biodynamics across scales.
    DOI:  https://doi.org/10.1038/s41467-022-35733-0
  13. JCI Insight. 2022 Dec 27. pii: e163397. [Epub ahead of print]
    TRPM7 kinase is required for insulin production and compensatory islet responses during obesity.
    Noushafarin Khajavi, Andreas Beck, Klea Ricku, Philipp Beyerle, Katharina Jacob, Sabrina F Syamsul, Anouar Belkacemi, Peter S Reinach, Pascale Cf Schreier, Houssein Salah, Tanja Popp, Aaron Novikoff, Andreas Breit, Vladimir Chubanov, Timo D Müller, Susanna Zierler, Thomas Gudermann.
      Most overweight individuals do not develop diabetes due to compensatory islet responses to restore glucose homeostasis. Therefore, regulatory pathways that promote β-cell compensation are potential targets for treatment of diabetes. The melastatin transient receptor potential 7 protein (TRPM7), harboring a cation channel and a serine/threonine kinase, has been implicated in controlling cell growth and proliferation. Here, we report that selective deletion of Trpm7 in β-cells disrupts insulin secretion and leads to progressive glucose intolerance. We indicate that the diminished insulinotropic response in β-cell-specific Trpm7 knockout mice is caused by decreased insulin production due to an impaired enzymatic activity of this protein. Accordingly, high-fat fed mice with a genetic loss of TRPM7 kinase activity (Trpm7R/R) display a marked glucose intolerance accompanied by hyperglycemia. These detrimental glucoregulatory effects are engendered by reduced compensatory β-cell responses due to mitigated AKT/ERK signaling. Collectively, our data identify TRPM7 kinase as a novel regulator of insulin synthesis, β-cell dynamics, and glucose homeostasis under obesogenic diet.
    Keywords:  Beta cells; Cell Biology; Insulin; Ion channels
    DOI:  https://doi.org/10.1172/jci.insight.163397
  14. EMBO Rep. 2022 Dec 27. e55843
    A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation.
    Qiuying Liu, Mariah K Novak, Rachel M Pepin, Katharine R Maschhoff, Kailey Worner, Xiaoli Chen, Shaojie Zhang, Wenqian Hu.
      Congenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH; however, the molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model, we reveal that the mouse R783H mutation (R796H in human) alters Trim71's mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. Mutant Trim71, but not wild-type Trim71, binds Lsd1 (Kdm1a) mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.
    Keywords:  Lsd1; RNA-binding protein; Trim71; congenital hydrocephalus; embryonic stem cell
    DOI:  https://doi.org/10.15252/embr.202255843
  15. FASEB J. 2023 Feb;37(2): e22730
    Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue.
    Ruojun Qiu, Shuo Wang, Dingyi Lin, Yingzi He, Shaohan Huang, Beibei Wu, Hong Li, Min Wang, Fenping Zheng.
      The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3-L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype. We found that a heterozygous R133L mutation in LMNA induced most of the metabolic disturbances seen in patients with this mutation, including ectopic lipid accumulation, limited subcutaneous adipose tissue (SAT) expansion, and insulin resistance. Mitochondrial dysfunction and senescence promote ectopic lipid accumulation and insulin resistance. In addition, the FLAG-mediated pull-down capture followed by mass spectrometry assay showed that p160 Myb-binding protein (P160 MBP; Mybbp1 a $$ a $$ ), the critical transcriptional repressor of PGC-1α, was bound to lamin A/C. Increased Mybbp1 a $$ a $$ levels in tissues and greater Mybbp1 a $$ a $$ -lamin A/C binding in nuclear inhibit PGC-1α activity and promotes mitochondrial dysfunction. Our findings confirm that the novel R133L heterozygous mutation in the LMNA gene caused APS are associated with marked mitochondrial respiratory chain impairment, which were induced by decreased PGC-1α levels correlating with increased Mybbp1a levels in nuclear, and a senescence phenotype of the subcutaneous fat.
    Keywords:  Lamin A/C; Mybbp1a; PGC1α; ectopic lipid accumulation; lipodystrophy; mitochondrial dysfunction
    DOI:  https://doi.org/10.1096/fj.202201252RR
  16. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2120582120
    Genetic dissection of intercellular interactions in vivo by membrane-permeable protein.
    Shaohua Zhang, Qianyu Zhang, Zixin Liu, Kuo Liu, Lingjuan He, Kathy O Lui, Lixin Wang, Bin Zhou.
      Unraveling cell-cell interaction is fundamental to understanding many biological processes. To date, genetic tools for labeling neighboring cells in mammals are not available. Here, we developed a labeling strategy based on the Cre-induced intercellular labeling protein (CILP). Cre-expressing donor cells release a lipid-soluble and membrane-permeable fluorescent protein that is then taken up by recipient cells, enabling fluorescent labeling of neighboring cells. Using CILP, we specifically labeled endothelial cells surrounding a special population of hepatocytes in adult mice and revealed their distinct gene signatures. Our results highlight the potential of CILP as a platform to reveal cell-cell interactions and communications in vivo.
    Keywords:  genetic tool; intercellular interactions; liver zonation; membrane-permeable protein; niche
    DOI:  https://doi.org/10.1073/pnas.2120582120
  17. Nat Commun. 2022 Dec 26. 13(1): 7951
    Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats.
    Jesus Paez-Mayorga, Jocelyn Nikita Campa-Carranza, Simone Capuani, Nathanael Hernandez, Hsuan-Chen Liu, Corrine Ying Xuan Chua, Fernanda Paola Pons-Faudoa, Gulsah Malgir, Bella Alvarez, Jean A Niles, Lissenya B Argueta, Kathryn A Shelton, Sarah Kezar, Pramod N Nehete, Dora M Berman, Melissa A Willman, Xian C Li, Camillo Ricordi, Joan E Nichols, A Osama Gaber, Norma S Kenyon, Alessandro Grattoni.
      Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.
    DOI:  https://doi.org/10.1038/s41467-022-35629-z
  18. Nat Immunol. 2022 Dec 28.
    Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.
    Myeong Joon Kim, Kyungsoo Kim, Hyo Jin Park, Gil-Ran Kim, Kyeong Hee Hong, Ji Hoon Oh, Jimin Son, Dong Jin Park, Dahae Kim, Je-Min Choi, Insuk Lee, Sang-Jun Ha.
      Regulatory T (Treg) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP-Cre-ERT2(+/-) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg cell numbers, but did not directly restore the cytokine production of TI CD8+ T cells in TC-1 lung cancer. Single-cell analysis indicated that PD-1 signaling promoted lipid metabolism, proliferation and suppressive pathways in TI Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.
    DOI:  https://doi.org/10.1038/s41590-022-01373-1
  19. Nat Immunol. 2022 Dec 28.
    SREBP signaling is essential for effective B cell responses.
    Wei Luo, Julia Z Adamska, Chunfeng Li, Rohit Verma, Qing Liu, Thomas Hagan, Florian Wimmers, Shakti Gupta, Yupeng Feng, Wenxia Jiang, Jiehao Zhou, Erika Valore, Yanli Wang, Meera Trisal, Shankar Subramaniam, Timothy F Osborne, Bali Pulendran.
      Our previous study using systems vaccinology identified an association between the sterol regulatory binding protein (SREBP) pathway and humoral immune response to vaccination in humans. To investigate the role of SREBP signaling in modulating immune responses, we generated mice with B cell- or CD11c+ antigen-presenting cell (APC)-specific deletion of SCAP, an essential regulator of SREBP signaling. Ablation of SCAP in CD11c+ APCs had no effect on immune responses. In contrast, SREBP signaling in B cells was critical for antibody responses, as well as the generation of germinal centers,memory B cells and bone marrow plasma cells. SREBP signaling was required for metabolic reprogramming in activated B cells. Upon mitogen stimulation, SCAP-deficient B cells could not proliferate and had decreased lipid rafts. Deletion of SCAP in germinal center B cells using AID-Cre decreased lipid raft content and cell cycle progression. These studies provide mechanistic insights coupling sterol metabolism with the quality and longevity of humoral immunity.
    DOI:  https://doi.org/10.1038/s41590-022-01376-y
  20. Cell Death Dis. 2022 Dec 26. 13(12): 1072
    Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis.
    Jiawei Guo, Zihao Song, Jie Yu, Chengyi Li, Chenchen Jin, Wei Duan, Xiu Liu, Yingying Liu, Shuai Huang, Yonghua Tuo, Fei Pei, Zhengyang Jian, Pengyu Zhou, Shaoyi Zheng, Zhaowei Zou, Feng Zhang, Quan Gong, Sijia Liang.
      Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca2+-activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A-GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A-GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A-GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.
    DOI:  https://doi.org/10.1038/s41419-022-05518-w
  21. Nat Commun. 2022 12 26. 13(1): 7940
    Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.
    Evangelia Lekka, Aleksandra Kokanovic, Simone Mosole, Gianluca Civenni, Sandro Schmidli, Artur Laski, Alice Ghidini, Pavithra Iyer, Christian Berk, Alok Behera, Carlo V Catapano, Jonathan Hall.
      Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop. The Lin28/let-7 axis resides at the interface of metabolic reprogramming and oncogenesis and is therefore a potential target for several diseases. In this study, we use compound-C1632, a drug-like Lin28 inhibitor, and show that the Lin28/let-7 axis regulates the balance between ketogenesis and lipogenesis in liver cells. Hence, Lin28 inhibition activates synthesis and secretion of ketone bodies whilst suppressing lipogenesis. This occurs at least partly via let-7-mediated inhibition of nuclear receptor co-repressor 1, which releases ketogenesis gene expression mediated by peroxisome proliferator-activated receptor-alpha. In this way, small-molecule Lin28 inhibition protects against lipid accumulation in multiple cellular and male mouse models of hepatic steatosis. Overall, this study highlights Lin28 inhibitors as candidates for the treatment of hepatic disorders of abnormal lipid deposition.
    DOI:  https://doi.org/10.1038/s41467-022-35481-1
  22. FASEB J. 2023 Feb;37(2): e22734
    ADAM10- and γ-secretase-dependent cleavage of the transmembrane protein PTPRT attenuates neurodegeneration in the mouse model of Alzheimer's disease.
    Siling Liu, Zhongyu Zhang, Lianwei Li, Li Yao, Zhanshan Ma, Jiali Li.
      PTPRT (receptor-type tyrosine-protein phosphatase T), a brain-specific type 1 transmembrane protein, plays an important role in neurodevelopment and synapse formation. However, whether abnormal PTPRT signaling is associated with Alzheimer's disease (AD) remains elusive. Here, we report that Ptprt mRNA expression is found to be downregulated in the brains of both human and mouse models of AD. We further identified that the PTPRT intracellular domain (PICD), which is released by ADAM10- and γ-secretase-dependent cleavage of PTPRT, efficiently translocates to the nucleus via a conserved nuclear localization signal (NLS). We show that inhibition of nuclear translocation of PICD leads to an accumulation of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a substrate of PTPRT-eventually resulting in neuronal cell death. Consistently, RNA sequencing reveals that overexpression of PICD leads to changes in the expression of genes that are functionally associated with synapse formation, cell adhesion, and protein dephosphorylation. Moreover, overexpression of PICD not only decreases the level of phospho-STAT3Y705 and amyloid β production in the hippocampus of APP/PS1 mice but also partially improves synaptic function and behavioral deficits in this mouse model of AD. These findings suggest that a novel role of the ADAM 10- and γ-secretase-dependent cleavage of PTPRT may alleviate the AD-like neurodegenerative processes.
    Keywords:  ADAM10; Alzheimer's disease; PTPRT; STAT3; presenilin 1/2; γ-Secretase
    DOI:  https://doi.org/10.1096/fj.202201396R
  23. J Biol Chem. 2022 Dec 22. pii: S0021-9258(22)01268-6. [Epub ahead of print] 102825
    Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
    Xingwen Wang, Yi Zhang, Qingyu Lin, Kunming Zhao, Dantong Zhu, Ying Hu.
      Long non-coding RNAs (lncRNAs) are emerging as essential players in multiple biological processes. Mitochondrial dynamics, comprising the continuous cycle of fission and fusion, are required for healthy mitochondria that function properly. Despite long-term recognition of its significance in cell-fate control, the mechanism underlying mitochondrial fusion is not completely understood, particularly regarding the involvement of lncRNAs. Here, we show that the lncRNA HITT (HIF-1α inhibitor at translation level), can specifically localize in mitochondria. Cells expressing higher levels of HITT contain fragmented mitochondria. Conversely, we show that HITT knockdown cells have more tubular mitochondria than is present in control cells. Mechanistically, we demonstrate HITT directly binds mitofusin-2 (MFN2), a core component that mediates mitochondrial outer membrane fusion, by the in vitro RNA pull-down and UV-cross-linking RNA-IP (CLIP) assays. In doing so, we found HITT disturbs MFN2 homo- or heterotypic complex formation, attenuating mitochondrial fusion. Under stress conditions, such as ultraviolet radiation, we in addition show HITT stability increases as a consequence of MiR-205 downregulation, inhibiting MFN2-mediated fusion and leading to apoptosis. Overall, our data provide significant insights into the roles of organelle (mitochondria)-specific resident lncRNAs in regulating mitochondrial fusion, and also reveal how such a mechanism controls cellular sensitivity to UV radiation-induced apoptosis.
    Keywords:  LINC00637; MFN2; apoptosis; mitochondrial dynamics; mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.jbc.2022.102825
  24. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01768-5. [Epub ahead of print]41(13): 111872
    Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch.
    Ashwini Hariharan, Colin D Robertson, Daniela C G Garcia, Thomas A Longden.
      Despite the abundance of capillary thin-strand pericytes and their proximity to neurons and glia, little is known of the contributions of these cells to the control of brain hemodynamics. We demonstrate that the pharmacological activation of thin-strand pericyte KATP channels profoundly hyperpolarizes these cells, dilates upstream penetrating arterioles and arteriole-proximate capillaries, and increases capillary blood flow. Focal stimulation of pericytes with a KATP channel agonist is sufficient to evoke this response, mediated via KIR2.1 channel-dependent retrograde propagation of hyperpolarizing signals, whereas genetic inactivation of pericyte KATP channels eliminates these effects. Critically, we show that decreasing extracellular glucose to less than 1 mM or inhibiting glucose uptake by blocking GLUT1 transporters in vivo flips a mechanistic energy switch driving rapid KATP-mediated pericyte hyperpolarization to increase local blood flow. Together, our findings recast capillary pericytes as metabolic sentinels that respond to local energy deficits by increasing blood flow to neurons to prevent energetic shortfalls.
    Keywords:  CP: Neuroscience; K(IR) channels; KATP channels; capillaries; cerebral blood flow; endothelial cells; energy; functional hyperemia; glucose; metabolism; neurovascular coupling; pericytes
    DOI:  https://doi.org/10.1016/j.celrep.2022.111872
  25. Cell Death Dis. 2022 Dec 27. 13(12): 1074
    Loss of tumor suppressor WWOX accelerates pancreatic cancer development through promotion of TGFβ/BMP2 signaling.
    Hussam Husanie, Muhannad Abu-Remaileh, Kian Maroun, Lina Abu-Tair, Hazem Safadi, Karine Atlan, Talia Golan, Rami I Aqeilan.
      Pancreatic cancer is one of the most lethal cancers, owing to its late diagnosis and resistance to chemotherapy. The tumor suppressor WW domain-containing oxidoreductase (WWOX), one of the most active fragile sites in the human genome (FRA16D), is commonly altered in pancreatic cancer. However, the direct contribution of WWOX loss to pancreatic cancer development and progression remains largely unknown. Here, we report that combined conditional deletion of Wwox and activation of KRasG12D in Ptf1a-CreER-expressing mice results in accelerated formation of precursor lesions and pancreatic carcinoma. At the molecular level, we found that WWOX physically interacts with SMAD3 and BMP2, which are known activators of the TGF-β signaling pathway. In the absence of WWOX, TGFβ/BMPs signaling was enhanced, leading to increased macrophage infiltration and enhanced cancer stemness. Finally, overexpression of WWOX in patient-derived xenografts led to diminished aggressiveness both in vitro and in vivo. Overall, our findings reveal an essential role of WWOX in pancreatic cancer development and progression and underscore its role as a bona fide tumor suppressor.
    DOI:  https://doi.org/10.1038/s41419-022-05519-9
  26. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2213846120
    Piezo mechanosensory channels regulate centrosome integrity and mitotic entry.
    Liron David, Laurel Martinez, Qiongchao Xi, Kameron A Kooshesh, Ying Zhang, Jagesh V Shah, Richard L Maas, Hao Wu.
      Piezo1 and 2 are evolutionarily conserved mechanosensory cation channels known to function on the cell surface by responding to external pressure and transducing a mechanically activated Ca2+ current. Here we show that both Piezo1 and 2 also exhibit concentrated intracellular localization at centrosomes. Both Piezo1 and 2 loss-of-function and Piezo1 activation by the small molecule Yoda1 result in supernumerary centrosomes, premature centriole disengagement, multi-polar spindles, and mitotic delay. By using a GFP, Calmodulin and M13 Protein fusion (GCaMP) Ca2+-sensitive reporter, we show that perturbations in Piezo modulate Ca2+ flux at centrosomes. Moreover, the inhibition of Polo-like-kinase 1 eliminates Yoda1-induced centriole disengagement. Because previous studies have implicated force generation by microtubules as essential for maintaining centrosomal integrity, we propose that mechanotransduction by Piezo maintains pericentrosomal Ca2+ within a defined range, possibly through sensing cell intrinsic forces from microtubules.
    Keywords:  Ca2+ signaling; centrioles; centrosomes; mechanotransduction; piezo
    DOI:  https://doi.org/10.1073/pnas.2213846120
  27. Cell. 2022 Dec 18. pii: S0092-8674(22)01506-9. [Epub ahead of print]
    Clonal replacement sustains long-lived germinal centers primed by respiratory viruses.
    Renan V H de Carvalho, Jonatan Ersching, Alexandru Barbulescu, Alvaro Hobbs, Tiago B R Castro, Luka Mesin, Johanne T Jacobsen, Brooke K Phillips, Hans-Heinrich Hoffmann, Roham Parsa, Maria Cecilia C Canesso, Carla R Nowosad, Allan Feng, Sarah R Leist, Ralph S Baric, Emily Yang, P J Utz, Gabriel D Victora.
      Germinal centers (GCs) form in secondary lymphoid organs in response to infection and immunization and are the source of affinity-matured B cells. The duration of GC reactions spans a wide range, and long-lasting GCs (LLGCs) are potentially a source of highly mutated B cells. We show that rather than consisting of continuously evolving B cell clones, LLGCs elicited by influenza virus or SARS-CoV-2 infection in mice are sustained by progressive replacement of founder clones by naive-derived invader B cells that do not detectably bind viral antigens. Rare founder clones that resist replacement for long periods are enriched in clones with heavily mutated immunoglobulins, including some with very high affinity for antigen, that can be recalled by boosting. Our findings reveal underappreciated aspects of the biology of LLGCs generated by respiratory virus infection and identify clonal replacement as a potential constraint on the development of highly mutated antibodies within these structures.
    Keywords:  B cells; Immunology; SARS-CoV-2; clonal dynamics; germinal centers; influenza; viruses
    DOI:  https://doi.org/10.1016/j.cell.2022.11.031
  28. Cell Death Discov. 2022 Dec 30. 8(1): 504
    MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of β1-adrenergic receptor/β-arrestin signaling and controls a unique transcriptome.
    Bruno Moukette, Satoshi Kawaguchi, Marisa N Sepulveda, Taiki Hayasaka, Tatsuya Aonuma, Suthat Liangpunsakul, Lei Yang, Rohan Dharmakumar, Simon J Conway, Il-Man Kim.
      The β1-adrenergic receptor (β1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and β-arrestin-mediated β1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by β-arrestin-mediated β1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of β-arrestin-mediated β1AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant β1AR (G protein-coupled receptor kinase [GRK]-β1AR that exhibits impairment in β-arrestin-mediated β1AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK-β1AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of β1AR/β-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to β1AR/β-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.
    DOI:  https://doi.org/10.1038/s41420-022-01295-9
  29. Aging Cell. 2022 Dec 24. e13761
    P2Y6 receptor-dependent microglial phagocytosis of synapses mediates synaptic and memory loss in aging.
    Jacob M Dundee, Mar Puigdellívol, Richard Butler, Thomas O J Cockram, Guy C Brown.
      Aging causes loss of brain synapses and memory, and microglial phagocytosis of synapses may contribute to this loss. Stressed neurons can release the nucleotide UTP, which is rapidly converted into UDP, that in turn activates the P2Y6 receptor (P2Y6 R) on the surface of microglia, inducing microglial phagocytosis of neurons. However, whether the activation of P2Y6 R affects microglial phagocytosis of synapses is unknown. We show here that inactivation of P2Y6 R decreases microglial phagocytosis of isolated synapses (synaptosomes) and synaptic loss in neuronal-glial co-cultures. In vivo, wild-type mice aged from 4 to 17 months exhibited reduced synaptic density in cortical and hippocampal regions, which correlated with increased internalization of synaptic material within microglia. However, this aging-induced synaptic loss and internalization were absent in P2Y6 R knockout mice, and these mice also lacked any aging-induced memory loss. Thus, P2Y6 R appears to mediate aging-induced loss of synapses and memory by increasing microglial phagocytosis of synapses. Consequently, blocking P2Y6 R has the potential to prevent age-associated memory impairment.
    Keywords:  P2Y6 receptor; aging; memory; microglia; phagocytosis
    DOI:  https://doi.org/10.1111/acel.13761
  30. Nat Cancer. 2022 Dec 29.
    An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia.
    Audrey Lasry, Bettina Nadorp, Maarten Fornerod, Deedra Nicolet, Huiyun Wu, Christopher J Walker, Zhengxi Sun, Matthew T Witkowski, Anastasia N Tikhonova, Maria Guillamot-Ruano, Geraldine Cayanan, Anna Yeaton, Gabriel Robbins, Esther A Obeng, Aristotelis Tsirigos, Richard M Stone, John C Byrd, Stanley Pounds, William L Carroll, Tanja A Gruber, Ann-Kathrin Eisfeld, Iannis Aifantis.
      Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive census of the bone marrow immune microenvironment in adult and pediatric patients with AML. We characterize unique inflammation signatures in a subset of AML patients, associated with inferior outcomes. We identify atypical B cells, a dysfunctional B-cell subtype enriched in patients with high-inflammation AML, as well as an increase in CD8+GZMK+ and regulatory T cells, accompanied by a reduction in T-cell clonal expansion. We derive an inflammation-associated gene score (iScore) that associates with poor survival outcomes in patients with AML. Addition of the iScore refines current risk stratifications for patients with AML and may enable identification of patients in need of more aggressive treatment. This work provides a framework for classifying patients with AML based on their immune microenvironment and a rationale for consideration of the inflammatory state in clinical settings.
    DOI:  https://doi.org/10.1038/s43018-022-00480-0
  31. Nat Immunol. 2022 Dec 29.
    SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.
    Anthos Christofides, Xanthi-Lida Katopodi, Carol Cao, Dimitra Karagkouni, Konstantinos Aliazis, Sasitorn Yenyuwadee, Halil-Ibrahim Aksoylar, Rinku Pal, Mohamed A A Mahmoud, Laura Strauss, Natalia M Tijaro-Ovalle, Louis Boon, John Asara, Ioannis S Vlachos, Nikolaos Patsoukis, Vassiliki A Boussiotis.
      The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth. RNA sequencing (RNA-seq) followed by gene set enrichment analysis indicated the presence of polymorphonuclear myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) with enriched gene expression profiles of enhanced differentiation, activation and expression of immunostimulatory molecules. In mice with conditional targeting of PD-1 in myeloid cells, which also displayed diminished tumor growth, TAMs had gene expression profiles enriched for myeloid differentiation, activation and leukocyte-mediated immunity displaying >50% overlap with enriched profiles of SHP-2-deficient TAMs. In bone marrow, GM-CSF induced the phosphorylation of PD-1 and recruitment of PD-1-SHP-2 to the GM-CSF receptor. Deletion of SHP-2 or PD-1 enhanced GM-CSF-mediated phosphorylation of the transcription factors HOXA10 and IRF8, which regulate myeloid differentiation and monocytic-moDC lineage commitment, respectively. Thus, SHP-2 and PD-1-SHP-2 signaling restrained myelocyte differentiation resulting in a myeloid landscape that suppressed antitumor immunity.
    DOI:  https://doi.org/10.1038/s41590-022-01385-x
  32. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2203779120
    Bone marrow-derived IGF-1 orchestrates maintenance and regeneration of the adult skeleton.
    Jianfang Wang, Qiaoling Zhu, Dandan Cao, Qiqi Peng, Xiaoying Zhang, Chong Li, Chen Zhang, Bo O Zhou, Rui Yue.
      Insulin-like growth factor I (IGF-1) is a key regulator of tissue growth and development in response to growth hormone stimulation. In the skeletal system, IGF-1 derived from osteoblasts and chondrocytes are essential for normal bone development; however, whether bone marrow (BM)-resident cells provide distinct sources of IGF-1 in the adult skeleton remains elusive. Here, we show that BM stromal cells (BMSCs) and megakaryocytes/platelets (MKs/PLTs) express the highest levels of IGF-1 in adult long bones. Deletion of Igf1 from BMSCs by Lepr-Cre leads to decreased bone formation, impaired bone regeneration, and increased BM adipogenesis. Importantly, reduction of BMSC-derived IGF-1 contributes to fasting-induced marrow fat accumulation. In contrast, deletion of Igf1 from MKs/PLTs by Pf4-Cre leads to reduced bone formation and regeneration without affecting BM adipogenesis. To our surprise, MKs/PLTs are also an important source of systemic IGF-1. Platelet-rich plasma (PRP) from Pf4-Cre; Igf1f/fmice showed compromised osteogenic potential both in vivo and in vitro, suggesting that MK/PLT-derived IGF-1 underlies the therapeutic effects of PRP. Taken together, this study identifies BMSCs and MKs/PLTs as two important sources of IGF-1 that coordinate to maintain and regenerate the adult skeleton, highlighting reciprocal regulation between the hematopoietic and skeletal systems.
    Keywords:  IGF-1; adipogenesis; bone marrow; hematopoiesis; osteogenesis
    DOI:  https://doi.org/10.1073/pnas.2203779120
  33. Immunity. 2022 Dec 19. pii: S1074-7613(22)00605-7. [Epub ahead of print]
    The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer.
    Andrew Chow, Fathema Z Uddin, Michael Liu, Anton Dobrin, Barzin Y Nabet, Levi Mangarin, Yonit Lavin, Hira Rizvi, Sam E Tischfield, Alvaro Quintanal-Villalonga, Joseph M Chan, Nisargbhai Shah, Viola Allaj, Parvathy Manoj, Marissa Mattar, Maximiliano Meneses, Rebecca Landau, Mariana Ward, Amanda Kulick, Charlene Kwong, Matthew Wierzbicki, Jessica Yavner, Jacklynn Egger, Shweta S Chavan, Abigail Farillas, Aliya Holland, Harsha Sridhar, Metamia Ciampricotti, Daniel Hirschhorn, Xiangnan Guan, Allison L Richards, Glenn Heller, Jorge Mansilla-Soto, Michel Sadelain, Christopher A Klebanoff, Matthew D Hellmann, Triparna Sen, Elisa de Stanchina, Jedd D Wolchok, Taha Merghoub, Charles M Rudin.
      Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.
    Keywords:  CD8(+) T cells; T cell receptors; immune checkpoint blockade; non-small cell lung cancer; tumor mutation burden
    DOI:  https://doi.org/10.1016/j.immuni.2022.12.001
  34. Nat Commun. 2022 12 24. 13(1): 7934
    Deconstructing body axis morphogenesis in zebrafish embryos using robot-assisted tissue micromanipulation.
    Ece Özelçi, Erik Mailand, Matthias Rüegg, Andrew C Oates, Mahmut Selman Sakar.
      Classic microsurgical techniques, such as those used in the early 1900s by Mangold and Spemann, have been instrumental in advancing our understanding of embryonic development. However, these techniques are highly specialized, leading to issues of inter-operator variability. Here we introduce a user-friendly robotic microsurgery platform that allows precise mechanical manipulation of soft tissues in zebrafish embryos. Using our platform, we reproducibly targeted precise regions of tail explants, and quantified the response in real-time by following notochord and presomitic mesoderm (PSM) morphogenesis and segmentation clock dynamics during vertebrate anteroposterior axis elongation. We find an extension force generated through the posterior notochord that is strong enough to buckle the structure. Our data suggest that this force generates a unidirectional notochord extension towards the tailbud because PSM tissue around the posterior notochord does not let it slide anteriorly. These results complement existing biomechanical models of axis elongation, revealing a critical coupling between the posterior notochord, the tailbud, and the PSM, and show that somite patterning is robust against structural perturbations.
    DOI:  https://doi.org/10.1038/s41467-022-35632-4
  35. Cell Discov. 2022 Dec 28. 8(1): 141
    Molecular mechanism of substrate recognition by folate transporter SLC19A1.
    Yu Dang, Dong Zhou, Xiaojuan Du, Hongtu Zhao, Chia-Hsueh Lee, Jing Yang, Yijie Wang, Changdong Qin, Zhenxi Guo, Zhe Zhang.
      Folate (vitamin B9) is the coenzyme involved in one-carbon transfer biochemical reactions essential for cell survival and proliferation, with its inadequacy causing developmental defects or severe diseases. Notably, mammalian cells lack the ability to de novo synthesize folate but instead rely on its intake from extracellular sources via specific transporters or receptors, among which SLC19A1 is the ubiquitously expressed one in tissues. However, the mechanism of substrate recognition by SLC19A1 remains unclear. Here we report the cryo-EM structures of human SLC19A1 and its complex with 5-methyltetrahydrofolate at 3.5-3.6 Å resolution and elucidate the critical residues for substrate recognition. In particular, we reveal that two variant residues among SLC19 subfamily members designate the specificity for folate. Moreover, we identify intracellular thiamine pyrophosphate as the favorite coupled substrate for folate transport by SLC19A1. Together, this work establishes the molecular basis of substrate recognition by this central folate transporter.
    DOI:  https://doi.org/10.1038/s41421-022-00508-w
  36. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2208525120
    SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression.
    Najla Arshad, Maudry Laurent-Rolle, Wesam S Ahmed, Jack Chun-Chieh Hsu, Susan M Mitchell, Joanna Pawlak, Debrup Sengupta, Kabir H Biswas, Peter Cresswell.
      Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein β2-microglobulin (β2m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells, these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8+ T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that down-regulate MHC-I expression to avoid CD8+ T cell recognition. Here, we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, down-regulate MHC-I expression using distinct mechanisms. First, ORF3a, a viroporin, reduces the global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β2m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a specific mechanism that allows immune evasion by SARS-CoV-2.
    Keywords:  SARS-CoV-2; antigen processing; immune evasion; molecular mimicry
    DOI:  https://doi.org/10.1073/pnas.2208525120
  37. Diabetes. 2022 Dec 29. pii: db220293. [Epub ahead of print]
    Elevated Adipocyte Membrane Phospholipid Saturation Does not Compromise Insulin Signaling.
    Henrik Palmgren, Kasparas Petkevicius, Stefano Bartesaghi, Andrea Ahnmark, Mario Ruiz, Ralf Nilsson, Lars Löfgren, Matthew S Glover, Anne-Christine Andréasson, Liselotte Andersson, Cécile Becquart, Michael Kurczy, Bengt Kull, Simonetta Wallin, Daniel Karlsson, Sonja Hess, Marcello Maresca, Mohammad Bohlooly-Y, Xiao-Rong Peng, Marc Pilon.
      Increased saturated fatty acid levels in membrane phospholipids have been implicated in the development of metabolic disease. Here, we tested the hypothesis that increased saturated fatty acid (SFA) content in cell membranes negatively impacts adipocyte insulin signaling. Pre-adipocyte cell models with elevated SFA levels in phospholipids were generated by disrupting the ADIPOR2 locus, which resulted in a striking two-fold increase in SFA-containing phosphatidylcholines and phosphatidylethanolamines, which persisted in differentiated adipocytes. Similar changes in phospholipid composition were observed in white adipose tissues isolated from the ADIPOR2 knockout mice. The SFA levels in phospholipids could be further increased by treating ADIPOR2-deficient cells with palmitic acid and resulted in reduced membrane fluidity and endoplasmic reticulum stress in mouse and human pre-adipocytes. Strikingly, increased SFA levels in differentiated adipocyte phospholipids had no effect on adipocyte gene expression or insulin signaling in vitro. Similarly, increased adipocyte phospholipid saturation did not impair white adipose tissue function in vivo, even in mice fed a high saturated fat diet at thermoneutrality. We conclude that increasing SFA levels in adipocyte phospholipids is well tolerated and does not affect adipocyte insulin signaling in vitro and in vivo.
    DOI:  https://doi.org/10.2337/db22-0293
  38. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2207250120
    SPOP loss of function protects against tauopathy.
    Randall J Eck, Rebecca L Kow, Aristide H Black, Nicole F Liachko, Brian C Kraemer.
      The pathological accumulation of the microtubule binding protein tau drives age-related neurodegeneration in a variety of disorders, collectively called tauopathies. In the most common tauopathy, Alzheimer's disease (AD), the accumulation of pathological tau strongly correlates with cognitive decline. The underlying molecular mechanisms that drive neurodegeneration in tauopathies remain incompletely understood and no effective disease modifying pharmacological interventions currently exist. Here, we show that tau toxicity depends on the highly conserved nuclear E3 ubiquitin ligase adaptor protein SPOP in a Caenorhabditis elegans model of tauopathy. Loss of function mutations in the C. elegans spop-1 gene significantly improves behavioral deficits in tau transgenic animals, while neuronal overexpression of SPOP-1 protein significantly worsens behavioral deficits. In addition, loss of spop-1 rescues a variety of tau-related phenotypes including the accumulation of total and phosphorylated tau protein, neurodegeneration, and shortened lifespan. Knockdown of SPOP-1's E3 ubiquitin ligase cul-3/Cullin3 does not improve tauopathy suggesting a non-degradative mechanism of action for SPOP-1. Suppression of disease-related phenotypes occurs independently of the nuclear speckle resident poly(A)-binding protein SUT-2/MSUT2. MSUT2 modifies tauopathy in mammalian neurons and in AD. Our work identifies SPOP as a novel modifier of tauopathy and a conceptual pathway for therapeutic intervention.
    Keywords:  Alzheimer's disease; C. elegans; neurodegeneration; tau; tauopathy
    DOI:  https://doi.org/10.1073/pnas.2207250120
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